Oral suspension of pharmaceutical substance

ABSTRACT

The present invention relates to orally administered suspensions of pharmaceutical active substances of the NSAID type, particularly the antirheumatic agent Meloxicam, which are stabilized by the addition of small amounts of highly dispersed silicon dioxide using high shear forces and adding small amounts of hydrophilic polymers to form a three-dimensional siloid structure, and a process for the preparation thereof.

This application is a continuation-in-part of prior provisionalapplication Ser. No. 60/084,498, filed May 6, 1998.

BACKGROUND OF THE INVENTION

The present invention relates to orally administered suspensions ofpharmaceutically active substances of the NSAID type(nonsteroidal-antiinflammatory drugs), but particularly theantirheumatic agent meloxicam and a process for preparing them.

Various pharmaceutical forms are used for oral administration of drugs.Thus, in addition to solid single-dose forms such as tablets, hard andsoft gelatin capsules, liquid forms such as solutions and syrups arealso given, in which the dose to be administered can be adjusted bymeans of the volume given.

Solutions and syrups have the advantage that they can be taken easilyand safely even by patients who have trouble taking solid, single-doseforms (e.g. children and older patients). Liquid preparations areadvantageously easy to measure out for veterinary use.

However, it should be borne in mind that even with the same dosage andthe same method of administration, the activity of the samepharmaceutical substance may vary. These variations mean that thetherapeutic effect clinically demonstrated for a drug in a specificpreparation cannot be achieved with a different preparation of the samedrug, and furthermore within a course of treatment one preparationcannot readily be exchanged for another. Preparations which are nottherapeutically equivalent are known as “non-bioequivalent”.For the oraladministration of pharmaceutical preparations, the drug is usuallyabsorbed faster from liquid preparations, particularly solutions, thanfrom tablets or capsules and these drugs are consequently not alwaysbioequivalent (Bauer K. H.; Frömming K. -H.; Führer C., PharmazeutischeTechnologie, 5^(th) Edition 1997, Gustav Fischer Verlag, Stuttgart, page213).

Meloxicam is an antirheumatic agent belonging to the NSAID's. NSAID'sare cyclooxygenase inhibitors, whilst meloxicam has been shown to have aselective inhibitory effect on the isoenzyme COX-2 and consequently areduced risk of undesirable gastrointestinal side effects. For safeadministration of meloxicam and other active substances, e.g. otherNSAID's, a liquid oral preparation is desirable as an alternative to thesolid form (capsule, tablet), particularly in pediatrics and inveterinary use.

The complex objective of the present invention was primarily to producean orally administered liquid preparation of meloxicam. The formulationshould take effect rapidly when first used in acute cases. However, thesubstance is preferably used for long-term therapy. In such long-termtherapy, the liquid oral formulation should be bioequivalent to otheroral formulations (tablet, capsule) in the steady state in order toallow therapy with either a liquid or solid oral formulation as desired.At the same time, the liquid preparation should have a pleasant flavorin order to be acceptable to children and thus ensure that it is takenas specified and the treatment is ensured. In addition, the liquidpreparation should preferably not contain any ethanol, since thepossibility of ethanol having a harmful effect even in physiologicallyacceptable, non-toxic concentrations cannot be ruled out completely,particularly in children. Moreover, when ethanol is used, there is therisk of abuse by alcohol-dependent patients or relapse on the part offormerly alcohol-dependent patients. The suitability of the formulationfor diabetic patients should also be taken into account. To ensure exactdosage of a liquid oral preparation of meloxicam, the preparation shouldalso be homogeneous over a sufficient length of time during its removalfrom the primary packaging.

In addition, the preparation should also be suitable for use in animals.The veterinary formulation should also have a smell and flavor which aresuitable for numerous types of animals which can be treated withantirheumatic drugs, particularly various species of mammals, to ensurethat the course of treatment is completed and the therapy is guaranteed,on the basis of good acceptance.

One obvious way of preparing a liquid oral formulation of apharmaceutically active substance is to dissolve the substance inphysiologically inert solvents (especially pharmaceutical grade water).However, this approach is unsuitable in many cases. To ensure thedesired pleasant taste of a liquid oral formulation, e.g. meloxicam, itis not possible to use solutions, since the substance in the dissolvedstate has an unpleasant taste of its own. This taste is apparent in allthe solvents which can be used for the oral administration of solutionsand cannot be adequately masked even by the addition of flavorcorrecting agents such as flavorings and sweeteners.

However, meloxicam does not have a noticeable flavor of its own when thesubstance is suspended in a physiologically inert dispersion medium fora liquid oral preparation and the solubility of meloxicam in thedispersion medium used is very slight. This provided a suitable approachto solving the problem. This approach can be applied analogously toother active substances of the NSAID category. Since a clearlynoticeable unpleasant taste is present even at a concentration of over500 μg/ml of dissolved meloxicam, the solubility of this activesubstance in the dispersion media used must be below this threshold.

When a suspension of active substance is used there is the problem thatthe homogeneity of the suspension has to be ensured for a sufficientlength of time during removal from the primary packaging (e.g. glassbottle, 100 ml) to ensure accurate dosing. However, the sedimentation ofsolids dispersed in liquid media cannot be prevented but only delayedfor a greater or lesser period. One conventional approach to delayingsedimentation is, for example, by increasing the viscosity of thedispersing medium by the addition of suitable substances, e.g. organichydrocolloid forming agents, e.g. cellulose ether, or silicon dioxide asa thickener. Increasing the viscosity of the dispersing agent does,however, have the serious disadvantage that it makes it considerablymore difficult to redisperse the sediment formed, to the extent that ifthe suspension is too viscous it is impossible to reconstitute thesuspension at all. Moreover, the caking caused by contact of theindividual particles under the effects of gravity during storage of thesuspension must be avoided. It is known from the literature to preventcaking by, for example, controlled flocculation of such systems by theadsorption of potential-determining ions (Sucker H., Fuchs P., SpeiserP., Pharmazeutische Technologie, 5^(th) Edition 1991, Georg ThiemeVerlag, Stuttgart, p. 423). The industrial manufacture of stablesuspensions by controlled flocculation is subject to limitations, sinceit is difficult to reproduce the optimum properties of suspensionsystems of this kind owing to the variability of the suspended solid andthe stability of the suspension is considerably affected by theadjuvants used.

BRIEF SUMMARY OF THE INVENTION

Surprisingly, the suspension of a pharmaceutically active substance ofthe NSAID type can be stabilised by the addition of small amounts ofhighly dispersed silicone dioxide in the presence of small amounts ofhydrophilic polymers. Because of the low concentration of highlydispersed silicon dioxide and hydrophilic polymer in the dispersionmedium, the viscosity is low; unwanted increased in viscosity, whichwill prevent reconstitution of the suspension, caused by gel-likethickening of the dispersion medium does not occur if at the same timesmall amounts of hydrophilic polymer which are soluble in the dispersionmedium are added to the medium and the silicon dioxide is added to thesuspension with the aid of high shear forces. Suitably high shear forcescan be produced with a suitable shear-intensive homogenising mixer, e.g.with mixers of the series “Becomix” made by Messrs. A. Berents GmbH &Co. KG, Henleinstr. 19, D-28816 Stuhr, which comprise rapidly rotatinghomogenizers working on the rotor-stator principle. A circumferentialrotor speed of about 25 to 27 m/s is particularly suitable forgenerating sufficiently high shear forces and is used to introduce thehighly dispersed silicon dioxide into the dispersing agent for about10-15 minutes, e.g. using the mixers Becomix RW 15/RW 60/RW 1000. Thisproduces a special siloid structure which consists of a spongythree-dimensional structure of hydratised highly dispersed silicondioxide shot through with cavities, the active substance being adsorbedonto said structure.

Suitable highly dispersed silicon dioxide has a specific surface area ofat least 50 m²/g, preferably 100 to 400 m²/g, for example, whilst aspecific surface area of about 200 m²/g is particularly preferred (e.g.Aerosil® 200).

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows two graphs displaying plasma levels of meloxicam after oraladministration of the suspension of the present invention and meloxicamadministered in a capsule dose.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to a suspension of a pharmaceutically activesubstance of the NSAID type with a suspendable particle size spectrum ina physiologically inert dispersion medium in which the active substancehas very little solubility, so that the suspension has no perceptibletaste of its own, for oral administration, characterised in that thesuspension contains a small amount of highly dispersed silicon dioxidefor stabilisation by forming a three-dimensional siloid structure, thethree-dimensional siloid structure being produced by adding the silicondioxide to the dispersion medium under the action of high shear forces,and the suspension additionally contains a small amount of hydrophilicpolymer which is soluble in the dispersion medium.

The above-mentioned three-dimensional siloid structure consists ofcrosslinked, swollen and coherent strands of SiO₂ between which can befound fairly large cavities filled with dispersion medium. The suspendedsolid particles of the active substance, e.g. meloxicam, are adsorbedalmost exclusively onto the SiO₂ strands. In this way, the suspendedparticles are rapidly and fully wetted and agglomeration of theparticles of pharmaceutical substance can be prevented entirely. Thisresults in a suspension of the active substance of exceptionalhomogeneity and dosing precision. The siloid structure described doesnot lead to any gel-like thickening of the dispersion medium but ratherproduces a low viscosity pourable suspension.

At the same time, the three-dimensional siloid structure acts as asedimentation stabiliser. The structure described is very bulky and iscompressed only slightly and very slowly even by sedimentation. Thus,even after months of storage, the volume of the siloid structuredecreases by only about 20%. The reduction in volume caused bysedimentation does not result in undesirable caking; the sediment can beeasily and quickly redispersed by the use of extremely slight mechanicalforces (e.g. very gentle shaking of an oral suspension of meloxicampackaged in standard commercial glass bottles). The slowness ofsedimentation ensures that the user has sufficient time to takehomogeneous single doses of the oral suspension of a pharmaceuticallyactive substance according to the invention out of its primarypackaging, thus ensuring accuracy of dosing.

For example, an active substance suspension according to the inventioncontains 0.1-5 wt. % of highly dispersed silicon dioxide (e.g. Aerosil®200), preferably 0.5-2 wt. %, more particularly 0.5-1.5 wt. %.

Suitable soluble hydrophilic polymers are pharmaceutical grade celluloseethers such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose(HPC) and hydroxypropylmethyl cellulose (HPMC). Hydroxyethyl celluloseis preferred. For example, a suspension of active substance according tothe invention contains 0.05-2 wt. % of water soluble cellulose ether,preferably 0.05-0.5 wt. %, but more particularly 0.05-0.1 wt. %.

Most preferably, the active substance suspension according to theinvention contains 0.5-1.5 wt. % of highly dispersed silicon dioxide and0.05-0.1 wt. % of hydroxyethyl cellulose.

The properties of a liquid oral suspension of active substance accordingto the invention are greatly influenced by the particle size of thesuspended active substance. To achieve the rapid onset of activity whichis desirable when the preparation is taken once, a small particle sizeis essential, ensuring the fastest possible dissolution of the activesubstance in gastrointestinal tract. In the particle size spectrum ofthe active substance which is suitable for a suspension according to theinvention, therefore, at least 90% of the particles are smaller than 50μm, preferably at least 50% of the particles are smaller than 10 μm, andmost preferably about 90% of the particles are smaller than 10 μm(determined for example by laser diffractometry). A correspondinglyfinely dispersed grade of pharmaceutical can easily be achieved bysuitably grinding a coarser grade. Suitable mills for grindingoperations of this kind are the standard commercial jet mills, forexample.

The small particle size of the active substance in a suspensionaccording to the invention as described also have the advantage of aslow rate of sedimentation of the suspended particles, which favorablyaffects the homogeneity of the liquid oral formulation of the activesubstance described and correspondingly ensures a high degree ofaccuracy in measuring the dose.

The solubility of the active substance in suitable physiologicallyacceptable dispersion media should be less than 500 μg/ml. Preferably,the solubility is not more than 50 μg/ml, most preferably the solubilityis not more than 5 μg/ml, but more particularly not more than 0.5 μg/ml.

It is readily possible for the skilled person to find, for any givenactive substance of the NSAID type, a suitable physiologicallyacceptable dispersion medium in which the active substance has thesolubility characteristics mentioned above. For meloxicam, thephysiologically acceptable dispersion medium preferably consists of anaqueous buffer system with a pH in the range from 2-4.

An orally administered suspension according to the invention may containone or more NSAID's as pharmaceutically active substance. The classicactive substance acetylsalicyclic acid and the active substances of thefollowing categories are mentioned as examples of NSAID'S:

(1) propionic acid derivatives,

(2) acetic acid derivatives,

(3) fenamic acid derivatives,

(4) biphenylcarboxylic acid derivatives,

(5) acid enolcarboxamides,

(6) diaryl heterocycles with methylsulphonyl or aminosulphonylsubstituents and

(7) acid sulphonamides.

The following active substances are mentioned as examples of propionicacid derivatives, although this list should not be regarded as limitingthis category of active substance:

ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen,indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen,tioxaprofen, suprofen, alminoprofen, tiaprofenic acid and fluprofen orthe pharmaceutically acceptable salts thereof.

Examples of acetic acid derivatives include the following activesubstances, although the list does not constitute any restriction ofthis category of active substance:

indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac,fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin,fentiazac, clidanac, etodolac and oxpinac or the pharmaceuticallyacceptable salts thereof.

The following active substances are mentioned as examples of fenamicacid derivatives, although the list does not constitute a limitation tothis category of active substance:

mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid andtolfenamic acid or the pharmaceutically acceptable salts thereof.

Examples of biphenylcarboxylic acid derivatives include the followingactive substances, although the list does not constitute a limitation ofthis category of active substance:

diflunisal and flufenisal or the pharmaceutically acceptable saltsthereof.

The following are examples of acid enolcarboxamides (oxicams), althoughthe list does not constitute a restriction to this category of activesubstance:

piroxicam, tenoxicam, lornoxicam and meloxicam or the pharmaceuticallyacceptable salts thereof.

Nimesulide is mentioned by way of example of an acid sulphonamide, butshould not constitute a restriction to this category of activesubstances.

Chemical structures, pharmacological activity, side effects andinformation regarding the usual dosage ranges for the above-mentionedNSAID's are given for example in Physician's Desk Reference, 35^(th)Edition, 1981; The Merck Index, 12^(th) Edition, Merck and Company,Rahway, N.J. (1996); Cutting's Handbook of Pharmacology, 6^(th) Edition,Ed. T. Z. Czacky, M.D., Appleton-Century-Crofts, New York, 1979, Chapter49:538-550.

A dosage unit for the following NSAID's may be, for example:

100-500 mg Diflunisal, 25-100 mg Zomepirac sodium, 50-400 mg Ibuprofen,125-500 mg Naproxen, 25-100 mg Flurbiprofen, 50-100 mg Fenoprofen, 10-20mg Piroxicam, 5-20 mg Meloxicam, 125-250 mg Mefenamic acid, 100-400 mgFenbufen and 25-50 mg Ketoprofen.

Particularly preferred oral administered suspensions according to theinvention are those which contain as active substance an acidenolcarboxamide, especially meloxicam.

Meloxicam is an NSAID with the structural type of an enolic acid andexhibits a distinctly pH-dependent solubility. The minimum solubility inbuffered aqueous systems is found at pH values from 2-4. The solubilityin this pH range is less than 0.5 μg/ml (Luger P., Daneck K., Engel W.,Trummlitz G., Wagner K., Structure and physicochemical properties ofmeloxicam, a new NSAID, Eur. J. Pharm. Sci. 4 (1996), 175-187).

Suitable dispersion media for a liquid oral suspension of meloxicamaccording to the invention are therefore physiologically acceptableaqueous buffer systems with a pH in the range from 2-4, mixtures thereofor mixtures thereof with other physiologically acceptable liquids whichare additionally suitable for improving specific properties of themeloxicam suspension, especially

for adjusting the viscosity of the dispersion medium in order to reducethe rate of sedimentation of the suspended particles of pharmaceutical,

to ensure that the liquid oral preparation has a pleasant flavor and

to improve the wetting qualities of the suspended pharmaceuticalparticles.

Other physiologically acceptable liquids in the sense of the inventiondescribed are preferably glycerol and optionally aqueous solutions ofsugar alcohols such as sorbitol, mannitol and xylitol, and mixturesthereof. In a suspension according to the invention these substanceshave the advantage

of increasing the viscosity of the dispersion medium and hence reducingthe rate of sedimentation of the suspended pharmaceutical particles andmaking it easier to handle when the liquid formulation is transferredinto metering aids (e.g. standard measuring spoons or special meteringsystems such as metering syringes) and when the liquid formulation ismeasured out in drops (e.g. standard dropper inserts),

of their slightly sweet inherent flavor which gives the liquid oralformulation a pleasant taste,

of their suitability for diabetic patients and animals which can betreated with antirheumatic drugs and

of improving the wetting properties of the suspended pharmaceuticalparticles.

Suitable physiologically acceptable aqueous buffer systems with a pH inthe range from 2-4 include, for example, sodium dihydrogen-phosphatedihydrate/citric acid monohydrate buffer, glycine/HCl (S. P. Sørensen,Biochem. Z., 21, 131 (1909); Biochem. Z., 22, 352 (1909)), Nacitrate/HCl(S. P. Sørensen, Biochem. Z., 21, 131 (1909); Biochem. Z., 22, 352(1909)), K-hydrogen phthalate/HCl (Clark and Lubs, J. Bact., 2, 1(1917)), citric acid/phosphate (T. C. McIlvaine, J. Biol. Chem., 49, 183(1921)), citrate-phosphate-borate/HCl (Teorell and Stenhagen, Biochem.Z., 299, 416 (1938)) and Britton-Robinson Buffer (Britton and Welford,J. Chem. Soc., 1, 1848 (1937)).

Preferably, a dispersion medium for a liquid oral suspension ofmeloxicam according to the invention is based on an aqueous buffersystem with a pH in the range from 2-4 mixed with one or more of thephysiologically acceptable liquids glycerol and aqueous solutions of thesugar alcohols mannitol, sorbitol and xylitol.

For example, the dispersion medium of a liquid oral suspension ofmeloxicam according to the invention consists of mixtures of about30-50% aqueous buffer system, pH 2-4, preferably aqueous sodiumdihydrogen phosphate dihydrate/citric acid monohydrate buffer, about10-20% glycerol, about 10-20% xylitol and about 20-30% sorbitol ormannitol solution (70% sorbitol or mannitol in water). Glycerol and theabove-mentioned sugar alcohols may be present either individually or inadmixture with one another in the dispersion medium.

The suspension ready for use may contain varying amounts of the activesubstance meloxicam, e.g. 0.050 to 3.000 g/118 g, preferably 0.050 to2.000 g/118 g, but particularly 0.050 to 1.5 g/118 g, based on the massof the preparation ready for use.

To improve the flavor still further, one or more flavorings and/or oneor more sweeteners may be added to a liquid oral suspension according tothe invention.

Suitable flavorings include, for example, liquid and powdered, watersoluble natural and nature-identical flavorings. Particularly preferredare liquid flavorings, particularly raspberry, strawberry and honey.

Suitable sweeteners include, for example, saccharin sodium, saccharin,cyclamate, acesulfam potassium and taumatin.

Moreover, conventional excipients and/or preservatives effective in thepH range, i.e. preferably sodium benzoate in the case of the activesubstance meloxicam, may be added to a liquid oral suspension accordingto the invention.

Because of the three-dimensional siloid structure and the adhesion ofthe suspended solid particles, there is no need to add any surfactantsto improve the wetting qualities. Surfactants may have a negative effectin suspensions since the solubility of the solid in the dispersionmedium may be increased in some cases, leading to an unwanted growth inparticle size. Moreover, surfactants, particularly ionic surfactants,are frequently allergenic and/or irritant to the mucous membranes.

The invention further relates to a process for producing an orallyadministered liquid preparation of a pharmaceutically active substanceof the NSAID type in the form of a stabilised suspension, characterisedin that

(i) the solid active substance is ground in order to produce a particlesize spectrum in which at least 90% of the particles are smaller than 50μm, preferably at least 50% of the particles are smaller than 10 μm, butin particular about 90% of the particles are smaller than 10 μm,

(ii) the ground active substance is suspended in a physiologically inertdispersion medium in which the solubility of the active substance isvery low,

(iii) small amounts of highly dispersed silicon dioxide are added to thedispersion medium with the application of high shear forces,

(iv) small amounts of hydrophilic polymer soluble in the dispersionmedium are added to the dispersion medium and

(v) optionally, one or more flavorings, one or more sweeteners,conventional excipients or one or more preservatives may, independentlyof one another, be added to the dispersion medium, the flavoringspreferably being added during the final stage of manufacture owing totheir foam breaking properties.

A preferred embodiment of the process according to the invention ischaracterised in that

(i) a particle size spectrum is produced in which about 90% of theparticles are smaller than 10 μm,

(ii) the ground active substance is suspended in a physiologicallyacceptable, aqueous buffer system at a pH in the range from 2-4, forexample sodium dihydrogen phosphate dihydrate/citric acid monohydratebuffer, glycine/HCl, K-hydrogen phthalate/HCl, citric acid/phosphate,citrate-phosphate-borate/HCl or Britton-Robinson buffer, mixturesthereof with one another or mixtures thereof with other physiologicallyacceptable liquids such as glycerol or optionally aqueous solutions ofsugar alcohols such as sorbitol, mannitol and xylitol,

(iii) with the aid of a mixer by the application of high shear forces,characterised for example by a circumferential rotor speed of 15-35 m/s,preferably 20-30 m/s, 0.1-5.0 wt.-% of highly dispersed silicon dioxide,based on the weight of the suspension ready for use, are added to thedispersion medium,

(iv) water soluble cellulose ethers of pharmaceutical grade are added tothe dispersion medium as hydrophilic polymers in an amount of from0.05-2 wt.-%, based on the weight of the suspension ready for use, and

(v) one or more flavorings, one or more sweeteners, conventionalexcipients or one or more preservatives may optionally be addedindependently of one another to the dispersion medium.

A particularly preferred embodiment of the process according to theinvention is characterised in that

(i) a particle size spectrum is produced in which about 90% of theparticles are smaller than 10 μm,

(ii) the ground active substance is suspended in a dispersion mediumconsisting of mixtures of 30-50% aqueous buffer systems with a pH in therange from 2-4, aqueous sodium dihydrogen phosphate dihydrate/citricacid monohydrate buffer being preferred, 10-20% glycerol, 10-20% xylitoland 20-30% sorbitol or mannitol solution (70% sorbitol or mannitol inwater), whilst glycerol and the above-mentioned sugar alcohols may bepresent in the dispersion medium either individually or in admixturewith one another,

(iii) 0.5-2.0 wt.-% of highly dispersed silicon dioxide, based on theweight of the suspension ready for use, are added to the dispersionmedium with the aid of a mixer by applying high shear forces,characterised for example by a circumferential rotor speed of 20 to 30m/s, preferably about 25 to 27 m/s,

(iv) pharmaceutical grade water-soluble cellulose ethers, preferablyhydroxyethyl cellulose, are added to the dispersion medium ashydrophilic polymers, in an amount of from 0.05-0.5 wt.-%, based on theweight of the suspension ready for use, and

(v) one or more flavorings, one or more sweeteners, conventionalexcipients or one or more preservatives may optionally be added to thedispersion medium independently of one another.

In all the above-mentioned embodiments of the process, steps (ii) to (v)are preferably carried out in vacuo since the entry of air affects thedensity of the suspension to be produced, as a result of floatingeffects or air absorption on the siloid structure, and inhomogeneitiesmay be produced.

A particularly preferred embodiment of the process according to theinvention is characterised in that the active substance is an acidenolcarboxamide, particularly meloxicam.

A third object of the invention is the use of an active substance of theNSAID type, preferably an acid enolcarboxamide, but particularlymeloxicam, for preparing a liquid preparation of the active substance inthe form of a stabilised suspension with a particle size spectrumwherein at least 90% of the particles are smaller than 50 μm, in aphysiologically inert dispersion medium in which the active substancehas very low solubility, so that the suspension does not have anynoticeable taste, for oral administration, characterised in that thesuspension contains a small amount of highly dispersed silicon dioxidefor stabilising it by forming a three-dimensional siloid structure, thethree-dimensional siloid structure being produced by adding the silicondioxide to the dispersion medium with the action of high shear forces,and the suspension additionally contains a small amount of hydrophilicpolymer soluble in the dispersion medium.

EXAMPLE

The following recipe is for the preparation of 100 ml of a liquid,orally administered suspension of meloxicam according to the invention.The formulation makes it possible to take several doses of 7.5 mg ofmeloxicam in a volume of 5 ml from a suitably sized glass bottle bypouring into standard plastic measuring spoons. The ingredients whichare relevant to the effectiveness and the formation of the siloidstructure according to the invention are given quantitatively, whilstall the other ingredients may be present in the formulation inaccordance with the information provided above.

In order to protect it from microbial contamination during use(multi-dose container) the preparation must be suitably preserved with apreservative (in this case sodium benzoate) adapted to the pH range ofthe dispersion medium.

Formulation A Formulation B g/100 ml g/100 ml Ingredient (= g/118 g) (=g/118 g) (1) Meloxicam, 0.150 1.500 jet-ground (2) Silicion dioxide,1.000 1.500 Highly dispersed (3) Hydroxyethylcellulose 0.100 0.050

Other ingredients are:

70% sorbitol solution (non-crystalline), 85% glycerol, xylitol, sodiumdihydrogen phosphate dihydrate, citric acid monohydrate, saccharinsodium crystals, sodium benzoate and raspberry flavoring D 9599(formulation A) or honey flavoring 203108 (formulation B). The mixtureis made up to a final volume of 100 ml, corresponding to 118.000 g, withpurified water.

Physical/chemical Properties of the Preparations

Formulation A Formulation B pH: 3.5-4.5 3.5-4.5 Density: 1.16-1.20 g/ml(20° C.) 1.16-1.20 g/ml (20° C.) Viscosity: 40-150 mPas 60-200 mPas

Pharmacokinetic Properties of the Preparation

A main objective for developing a liquid oral formulation of meloxicamwas the rapid onset of activity on first use. The prerequisite for thisis the fastest possible flooding of the drug into the central bloodcompartment.

In the formulation according to the above Example this is achieved. In adirect comparison between a suspension according to the invention and acapsule containing the same dose, the time for maximum plasmaconcentration on a single dose of meloxicam is t_(max=)2 h (1.5-5 h;suspension) as against t_(max=)5 h (2-6 h; capsule).

In the steady state, bioequivalence should be detectable owing to thedesired therapeutic equivalents of the suspension according to theinvention and a solid oral formulation. This has been shown by directcomparison of a suspension according to the invention with a capsulecontaining the same dose. In the steady state the maximum plasma levelsare at t_(max (ss))=5.0 h (5-9 h; suspension) and t_(max (ss))=5.0 h(3-7 h; capsule). A graphic representation of the results of the studyis shown in FIG. 1.

Method of Preparation

Suspensions according to the invention can be prepared by a multi-stagemixing and homogenising process. The use of shear-intensive homogenisingmixers which enable the solid particles of the active substance whichare to be suspended and the highly dispersed silicon dioxide to bedistributed in the dispersion medium within a very short time is crucialto the production of a homogeneous suspension having the siloidstructure described. Different sizes of process mixers from the series“Becomix” (made by Messrs. A. Berents GmbH & Co. KG, Henleinstr. 19,D-28816 Stuhr) have proved particularly suitable for this purpose andwill produce suspensions according to the invention in batch sizesranging from 2.5 to 1,000 kg. These mixers incorporate fast rotatinghomogenizers working on the rotor-stator principle which ensure optimummixing and production of the three-dimensional siloid structuredescribed above. Sufficiently high shear forces are generated, forexample, at a circumferential rotor speed of 20 to 30 m/s, preferablyabout 25 to 27 m/s. With the mixers Becomix RW 60/RW 1000,circumferential rotor speeds of about 26 m/s are used for about 10-15minutes to introduce the highly dispersed silicon dioxide into thedispersing agent.

Step 1 (Premix)

The active substance and the highly dispersed silicon dioxide arehomogeneously premixed in a suitable container (e.g. VA container). Thispremixing is necessary in order to achieve better wetting properties ofthe pharmaceutical substance and lump-free distribution in thesuspension.

Step 2 (Polymer Solution)

The majority of the water is placed in a suitable batch container (e.g.Becomix mixer) and the HEC is sucked in with stirring, homogenizationand in vacuo and then the mixture is stirred for about 10 minutes invacuo. The HEC is allowed to swell for about 30 min. at room temperature(RT) before heating to about 80° C. in vacuo and maintaining for about 1hours at this temperature and cooling to RT again.

Step 3 (Sodium Benzoate Solution)

A small amount of the water is placed in a suitable batch container(e.g. VA container) and the sodium benzoate is dissolved therein withstirring.

Step 4 (Final Mixing)

The sodium benzoate solution (see above) and the other ingredients ofthe composition with the exception of the flavoring are added to thepolymer solution (sucked in under vacuum). The mixture is thenhomogenised. The mixture of active substance and silicon dioxide is thenadded in vacuo, with stirring and homogenization and the mixture ishomogenised for a further 10 minutes in vacuo. The high shear forcesdescribed are characterised, for example, in that the mixture of activesubstance and silicon dioxide in a 1000 kg batch is sucked into thecirculation in a mixer of the Becomix RW 1000 type at a rotor speed ofabout 3500 rpm (corresponding to a circumferential speed of about 26m/s) and then homogenised for 10 minutes. Finally, the flavoring isadded in vacuo, with stirring and homogenization. This method makes useof the foam-breaking properties of the flavoring, which shortens thesubsequent process of de-aerating the suspension (vacuum). Thesuspension can be transferred from the mixer into bulk containers underpressure.

What is claimed is:
 1. A pharmaceutical composition of matter which isan orally administered suspension comprising particles of anon-steroidal anti-inflammtory active substance selected from the acidenolcarboxamides (oxicams), and pharmaceutically acceptable saltsthereof, having a suspendable particle size spectrum in which at least90% of the particles are smaller than 50 μm, a physiologically inertdispersion medium in which the particles of active substance aresuspended and in which dispersion medium the active substance has asolubility of less than 500 μg/ml, about 0.1 to about 5% by weight ofhighly dispersed silicon dioxide having a specific surface area of atleast 50 m²/g, forming a three-dimensional siloid structure produced byadding the silicon dioxide to the dispersion medium with the action ofshear forces characterised by a circumferential rotor speed of about 15to 35 m/s, and about 0.05 to about 2% by weight of a hydrophilicpolymer, which polymer is soluble in the dispersion medium.
 2. Thepharmaceutical composition of matter as recited in claim 1 wherein theactive substance is selected from the group consisting of piroxicam,tenoxicam, lomoxicam, meloxicam and the pharmaceutically acceptablesalts thereof.
 3. The pharmaceutical composition of matter as recited inclaim 1 wherein the highly dispersed silicon dioxide is present in anamount of from about 0.5% to about 2% by weight.
 4. The pharmaceuticalcomposition of matter as recited in claim 1 wherein the hydrophilicpolymer is a pharmaceutical-grade water soluble cellulose ether.
 5. Thepharmaceutical composition of matter as recited in claim 4 wherein thecellulose ether is present in an amount of from about 0.05% to about0.5% by weight.
 6. The pharmaceutical composition of matter as recitedin claim 4 wherein the cellulose ether is selected from the groupconsisting of hydroxyethyl cellulose, hydroxypropyl cellulose andhydroxypropyl methyl cellulose.
 7. The pharmaceutical composition ofmatter as recited in claim 1 wherein at least about 50% of the particlesof active substance are smaller than about 10 μm.
 8. The pharmaceuticalcomposition of matter as recited in claim 1 wherein the active substanceis meloxicam and the dispersion medium is an aqueous buffer system witha pH in the range from about 2-4.
 9. The pharmaceutical composition ofmatter as recited in claim 8 wherein the dispersion medium is a mixtureof a physiologically acceptable aqueous buffer system with glycerol orwith an aqueous solution of one or more sugar alcohols selected from thegroup consisting of xylitol, sorbitol and mannitol.
 10. Thepharmaceutical composition of matter as recited in claim 8 wherein thedispersion medium is a buffer system from the group consisting of (a)sodium dihydrogen phosphate dihydrate/citric acid monohydrate, (b)glycin/HCl, (c) Na-citrate/HCl, (d) K-hydrogen phthalate/HCl, (e) citricacid/phosphate, (f) citrate-phosphate-borate/HCl and (g)Britton-Robinson buffer.
 11. The pharmaceutical composition of matter asrecited in claim 9 wherein the dispersion medium is a mixture of about30 to about 50% aqueous sodium dihydrogen phosphate dihydrate/citricacid mono-hydrate buffer, about 10 to about 20% glycerol, about 10 toabout 20% xylitol and about 20 to about 30% sorbitol or mannitolsolution, the sorbitol or mannitol solution being an about 70% aqueoussolution.
 12. The pharmaceutical composition of matter as recited inclaim 8 wherein the composition of matter comprises about 0.050 to about3.000 g of meloxicam in about 118 g of pharmaceutical composition ofmatter.
 13. The pharmaceutical composition of matter as recited in claim1 further comprising a flavoring agent, a sweetener, a preservative or amixture of such.